Cardiomyopathies in 100,000 genomes project: interval evaluation improves diagnostic yield and informs strategies for ongoing gene discovery

Figures

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  Fig. 1. Overview of analyses and sources of diagnoses for 272 paediatric cardiomyopathy probands with available genome sequencing data in 100,000 Genomes Project. Initial GEL analysis pipeline identified (partial) diagnoses for 62 probands; other potentially causative variants were identified by other researchers accessing the 100KGP data and reported via the diagnostic discovery pathway. In addition, we prioritised variants by identifying rare protein altering variants in a candidate gene list; identifying structural variants in a candidate gene list; reviewing all protein coding de novo variants where trio data was available; reviewing variants flagged as pathogenic or likely pathogenic by ClinVar; and reviewing top 5 Exomiser hits. GEL, Genomics England; P/LP, pathogenic/likely pathogenic; PAV, protein altering variant; SV, structural variant

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  Fig. 2. Venn diagram of genes associated with paediatric cardiomyopathy. Literature—genes identified in paediatric cardiomyopathy studies and case reports; PanelApp R135 green—genes on R135 paediatric or syndromic cardiomyopathy PanelApp panel v3.44 with the highest level of evidence; PanelApp Version 1—genes on the original versions of hypertrophic, dilated, left ventricular non-compaction and arrhythmogenic cardiomyopathy panels most likely applied to those recruited to 100,000 Genomes Project in 2015–2018; Other Panels—genes on 6 other paediatric cardiomyopathy panels including Invitae, GeneDx, Ambry, Laboratory for Molecular Medicine, PanelApp Australia and Amsterdam Genetics. See Additional file 1: Tables S1–S4 for full gene lists

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  Fig. 3. Workflow depicting the number of participants in 100,000 Genome Project (100KGP) queried and filtered for cardiomyopathy (main-programme_v16_2022-10–13). Participants were defined as paediatric if they met any of the following criteria: age at consent ≤ 16 years old; age at diagnosis ≤ 16 years old; age at onset between 1 and 16 years; age at first cardiology appointment (using hospital episode statistics (HES) outpatient codes 320 or 170) ≤ 16 years old. Primary CM: participants recruited under a specific cardiomyopathy disease category. Complex CM: participants recruited under a non-cardiomyopathy disease category with a human phenotype ontology (HPO) term containing ‘cardiomyopathy’. Diagnosis returned represents the number of probands designated as solved in 100KGP. CM, cardiomyopathy

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  Fig. 4. Percentages of different family structures at enrolment for paediatric and adult cardiomyopathy probands and ‘solved’ probands in 100,000 Genome Project (100KGP). Stacked bars are labelled with numbers of probands. Paediatric—paediatric probands with cardiomyopathy (CM); Paediatric solved—paediatric probands with CM and a molecular diagnosis; Adult—adult probands with CM; Adult solved—adult probands with CM and a molecular diagnosis. Singleton refers to a proband for whom no other family member was recruited, duo with other biological relative refers to a proband–non-parent pair, duo with mother or father refers to a proband-parent pair, families with three or more participants refers to a proband recruited with 3 or more biological relatives (but not both mother and father), and trio with mother and father refers to a proband and both parents ± other individuals from the family. Participants are labelled as ‘solved’ in 100KGP if they had a genetic diagnosis that explained their presenting disease

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  Fig. 5. Kaplan–Meier survival analysis for adult and paediatric probands with cardiomyopathy (CM) in 100,000 Genomes Project. a and b Comparing adults and children from diagnosis and birth respectively. c and d Comparing survival probability for adults with different CM diagnoses from diagnosis (c) and birth (d). e and f Comparing survival probability for children with different CM diagnoses from diagnosis (e) and birth (f). p values derived from a log rank test. DCM—dilated cardiomyopathy (probands recruited under DCM and any Mixed_CM or Mixed_other probands where at least 1 recruitment category was DCM); HCM—hypertrophic cardiomyopathy (probands recruited under HCM and any previous Mixed_CM or Mixed_other where at least 1 recruitment category was HCM); Other includes probands recruited under LVNC—left ventricular non-compaction cardiomyopathy or ARVC—arrhythmogenic right ventricular cardiomyopathy. Complex CM: probands recruited under a non-cardiomyopathy disease category, but with a human phenotype ontology (HPO) term containing ‘cardiomyopathy’

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  Fig. 6. Genes implicated in the solved paediatric (n = 52) and adult (n = 146) cardiomyopathy probands in 100,000 Genome Project split by recruitment disease categories: Primary—DCM, HCM, Other (which includes ARVC and LVNC) and Complex CM (participants recruited under a non-cardiomyopathy disease category but who have a human phenotype ontology (HPO) term containing ‘cardiomyopathy’). Labels on bars indicate number of probands. Genes are colour coded: black genes are on the current R135 CM panel ‘green’ list; grey genes are on the R135 CM panel ‘green’ list but are not robustly associated with the type of cardiomyopathy reported in the solved case, e.g. PKP2 and HCM; dark purple genes are not on the current R135 CM panel ‘green’ list but CM is a recognised feature of the associated disease (NDUFA4 and FKRP are on the ‘amber’ list); light purple genes in bold are not on the current R135 CM panel ‘green’ list and CM is not a recognised feature of the associated disease. Full variant details can be found in Tables S10 and S11. *One adult proband recruited under HCM has both a pathogenic variant in PKP2 and a likely pathogenic variant in LZTR1 (see Table S11 for details). R135 CM panel—NHS…

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  Fig. 7. Overview of analyses and sources of diagnoses for 272 paediatric cardiomyopathy probands with available genome sequencing data in 100,000 Genomes Project. Initial GEL analysis pipeline identified (partial) diagnoses for 62 probands; 11 probands had variants identified by other researchers and reported via the Genomics England diagnostic discovery pathway. In our re-analysis, 60 probands had 65 variants of interest identified by 5 methods: identifying rare protein altering variants in nuclear-encoded genes in a candidate list; identifying structural variants in a candidate gene list; reviewing all protein coding de novo variants where trio data was available; reviewing variants flagged as pathogenic or likely pathogenic by ClinVar; reviewing top 5 Exomiser hits. GEL, Genomics England; P/LP, pathogenic/likely pathogenic; PAV, protein altering variant; SV, structural variant; VUS, variant of uncertain significance